Recently novel Epstein-Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active EBV infection (CAEBV) and EBV-driven B-cell LPDs mainly affecting the elderly. To better define the pathogenesis, classification, and treatment of these disorders participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting organized by our group. In our own work we have described the spectrum of EBV-associated B-cell LPD observed in a western population without known immunodeficiency. As with the reports from Japan, most patients are of advanced age, generally older than 60 years. 116 cases were identified over a 7 year period and fell into five diagnostic categories: 1) lymph node based reactive hyperplasia with increased EBV-positive B-cells, 2) EBV-positive nodal B-cell lymphoproliferations resembling post-transplant LPD (PTLD), 3) EBV-positive extranodal B-cell lymphoproliferations resembling PTLD, 4) EBV-positive diffuse DLBCLs, and 5) EBV-positive B-cell proliferations resembling CHL. Twenty-eight patients had EBV-associated reactive lymphoid hyperplasia, with a median age of 67 years. The process was self-limited in most patients, with only one patient showing progression to a more aggressive lymphoproliferative process. All cases tested were polyclonal by IgH PCR. T-cell clonality or a restricted T-cell receptor gene rearrangement pattern was seen in 3 (11%) of the cases studied. This finding suggests a reduction in diversity of the T cell receptor repertoire, as reported by Khanna et al. Features included preserved architecture, and a broad spectrum in cell size of the EBV-positive cells with frequent localization to germinal centers. The median age was highest in patients with EBV-positive DLBCL (77 yrs), which included 11 nodal DLBCL and 4 nodal or extranodal plasmablastic lymphomas. There were 73 polymorphic B-cell lymphomas approximately equally divided between nodal and extranodal sites. Median ages were 73 and 76 years respectively. Seven cases, median age 79, histologically and phenotypically resembled CHL (CD30+;CD15+) but presented in sites unusual for CHL such as oral cavity (palate, gingiva, tongue, lips) and adrenal glands. Supporting the concept that a restricted T-cell response to EBV may be associated with defective immune response, approximately 20% of patients with either polymorphic B-cell lymphoma or DLBCL had evidence of a restricted clonal or oligoclonal T-cell response. We have also described a series of EBV associated mucosal and cutaneous lymphoproliferative lesions characterized by distinctive pathological and clinical features. Histology, immunophenotype, EBER in situ hybridization and clonality by PCR were assessed in 24 EBV positive circumscribed, ulcerative B-cell lymphoproliferations (LPs) associated with various types of immunosuppression (IS). The study group comprised 9 male and 15 female patients, median age 77 years (range 42-101). IS in 8 cases included azathioprine (AZA ), methotrexate (MTX) or cyclosporin-A (CyA) administered for rheumatoid arthritis (5), ulcerative colitis (1), sarcoidosis with myasthenia gravis (1) and systemic lupus erythematosus (1). 16 patients were considered immunosuppressed due to age related immunosenescence. The patients presented with isolated sharply circumscribed ulcers involving oropharyngeal mucosa (15), esophagus (1), colon (1), rectum (1) and skin (6). Histology showed polymorphous lesions harboring B-cell blasts with Hodgkin or Reed-Sternberg (RS) cell morphology. The B-cells showed reduced expression of CD20 with strong CD30 and EBER positivity in a background of abundant activated T-cells. CD15 was positive in 48% of cases (10/21). The pathological features were identical regardless of the anatomical site or cause of IS. PCR revealed 31% (5/16) clonal IgH rearrangements with 43% (6/14) and 29% (4/14) clonal and restricted T-cell patterns respectively. 26% of patients (5/19) received standard chemotherapy and/or radiotherapy. 47% of lesions (9/19) regressed spontaneously with no treatment and 16% (3/19) were characterized by relapsing and remitting course. All the medication related lesions (5/5) with available follow up responded to reduction of IS. All patients achieved complete remission with no disease associated deaths over a median follow up period of 20.5 months (range 3-72). EBV positive Mucocutaneous Ulcer (EBVMCU) is a clinico-pathological entity with frequent Hodgkin-like features and a self limited, indolent course, requiring conservative management. Association with various forms of IS implies a common pathogenetic mechanism, frequently involving restricted and clonal T-cell responses. The localized nature of the disease may be due to a minimal and localized lapse in immunosurveillance over EBV. We have also worked to established improved techniques for laser capture microdissection. Laser assisted microdissection (LAM) is increasingly performed to facilitate isolation of specific tumor cell populations for molecular profiling. In certain types of tissue, routine hematoxylin-eosin (H&amp;E) staining is inadequate for clear identification of target cells and therefore immunohistochemical labeling is required. Yet, the use of conventional immunohistochemistry (IHC) for LAM is complicated by two factors, the features of LAM membrane slides, and the effects of routine tissue processing employing formalin fixation and paraffin embedding. Here we describe a detailed protocol for preparation of membrane slides that employs UV irradiation at 254nm and poly-L-lysine coating, enabling successful antigen retrieval (AR) and IHC of formalin-fixed paraffin embedded (FFPE) specimens. Ten archival FFPE specimens [five primary mediastinal large B-cell lymphoma;and five classical Hodgkins lymphoma, nodular sclerosis subtype] were chosen to establish the protocol, using CD20 or CD30 antibodies, respectively. Testing distinct incubation times and antibody dilutions, we could demonstrate specific target cell staining with high reproducibility in all cases. In addition, we investigated the feasibility of immuno-guided LAM on three different LAM microscopes and evaluated their integrated automatic cell recognition software. To further validate the method, DNA quality after immuno-guided LAM was examined. Paired samples of microdissected tumor cells of H&amp;E or immunohistochemically stained tissue sections from the same specimen were analyzed by PCR for &amp;#946;-globin gene and CpG island methylation array. Both staining methods showed identical PCR amplicon patterns for the &amp;#946;-globin gene, and a strong correlation (r = 0.945 to r = 0.981) for CpG island methylation of 1505 analyzed sites in a series of five paired samples. These results demonstrate the validity and utility of our AR and IHC protocol for archival FFPE samples mounted on membrane slides for LAM. The use of this technique offers new opportunities to unravel the specific genomic alterations of human malignancies.